PROJECT ABSTRACT Most effective vaccines work by inducing a long-lived pool of B cell-derived antibody secreting cells (ASCs) that colonize the bone marrow and produce antibodies (Abs) specific for the vaccine antigens. Although vaccine-induced ASCs provide protection from infection, ASCs can also cause pathology in autoimmune, allergic and transplant patients. Despite the importance of ASCs in protection from infection and in exacerbating chronic disease, we know remarkably little regarding the signals that regulate the development of ASCs from their B cell precursors or the signals that control the lifespan of the ASCs. Therefore, if we wish to manipulate ASC numbers in the settings of both health and disease, there is a need to understand the transcriptional and epigenetic programming events that control commitment to the ASC lineage. There is also a need to identify the microenvironment-derived signals that modulate PC lineage programming so that we can intervene to block or facilitate the development of ASCs with particular functional attributes or lifespans. We recently found that T-bet, an IFN?-induced transcription factor, is expressed by germinal center B cells, ?pre- ASCs? and some, but not all, ASCs. We showed that T-bet regulates ASC development in vitro and in vivo and that T-bet expressing pre-ASCs are induced after vaccination and are expanded in some autoimmune patients. Interestingly, we demonstrated that the IFN? and T-bet regulated ASC developmental pathway is enhanced by IL-21 and repressed by IL-4. Based on these data, the central hypothesis that will be tested in this proposal is that the cytokine microenvironment and the transcription factors induced by those cytokines modulate the epigenetic programming of activated B cells to shape the phenotype, lifespan and functionality of the developing ASCs. The objectives of this proposal are to: (i) determine the molecular and epigenetic basis for T- bet mediated regulation of ASC development, (ii) determine how the cytokine microenvironment modulates ASC development from nave and memory human B cells and (iii) determine how the cytokine microenvironment and cytokine induced transcription factors influence ASC function and lifespan following vaccination. The proposed research is significant because we will, for the first time, mechanistically address how one cytokine-induced transcription factor, T-bet, remodels the epigenetic landscape of developing ASCs and influences their differentiation, function and survival. We will also determine whether we can influence the development, size and quality of the ASC response by altering the cytokine microenvironment. We expect that these studies will not only increase our understanding of the molecular underpinnings of ASC fate decisions, but may also lead to new methodologies to manipulate the development of ASCs in autoimmune and vaccinated individuals.